title: Design, synthesis, and in vitro antifungal activity of 1-[(4-substituted-benzyl)methylamino]-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ols.
abstract: As part of our studies focused on the design of 1-[((hetero)aryl- and piperidinylmethyl)amino]-2-phenyl-3-(1H-1,2,4-triazol-1-yl)propan-2-ols as antifungal agents, we report the development of new extended benzylamine derivatives substituted at the para position by sulfonamide or retrosulfonamide groups linked to alkyl or aryl chains. These molecules have broad-spectrum antifungal activities not only against Candida spp., including fluconazole-resistant strains, but also against a filamentous species (A. fumigatus). Concerning fluconazole resistance, selected compounds exhibit the capacity to overcome CDR and ERG11 gene upregulation and to maintain antifungal activity despite a recognized critical CYP51 substitution in C. albicans isolates. Synthesis, investigation of the mechanism of action by sterol analysis in a C. albicans strain, and structure-activity relationships (SARs) are reported.
authors.affiliation: Université de Nantes, Nantes Atlantique Universités, Département de Pharmacochimie, Cibles et Médicaments des Infections, de l'Immunité et du Cancer, IICIMED-EA 1155, UFR Sciences Pharmaceutiques, Nantes, France.
authors.forename: Rémi
authors.initials: R
authors.lastname: Guillon
authors.forename: Fabrice
authors.initials: F
authors.lastname: Pagniez
authors.forename: Francis
authors.initials: F
authors.lastname: Giraud
authors.forename: Damien
authors.initials: D
authors.lastname: Crépin
authors.forename: Carine
authors.initials: C
authors.lastname: Picot
authors.forename: Marc
authors.initials: M
authors.lastname: Le Borgne
authors.forename: Florent
authors.initials: F
authors.lastname: Morio
authors.forename: Muriel
authors.initials: M
authors.lastname: Duflos
authors.forename: Cédric
authors.initials: C
authors.lastname: Logé
authors.forename: Patrice
authors.initials: P
authors.lastname: Le Pape
mesh_terms: D058888:14-alpha Demethylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001232:Aspergillus fumigatus / Q000187:drug effects; D001665:Binding Sites; D002176:Candida albicans / Q000187:drug effects; D020134:Catalytic Domain; D003198:Computer Simulation; D015195:Drug Design; D008826:Microbial Sensitivity Tests; D020005:Propanols / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D058886:Sterol 14-Demethylase / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D058888:14-alpha Demethylase Inhibitors; D000935:Antifungal Agents; D020005:Propanols; D058886:Sterol 14-Demethylase; D013449:Sulfonamides; D014230:Triazoles; C560344:4-(((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)methylamino)methyl)-N-(phenyl)benzenesulfonamide; D000096926:Benzenesulfonamides; C045575:1,2,4-triazole